170-OR: Tamoxifen Treatment Causes Insulin Resistance in Obese Mice

Abstract

Breast cancer survivors treated with the selective estrogen receptor modulator tamoxifen have an elevated risk for developing type 2 diabetes (T2D) compared with cancer-free individuals, especially in the context of obesity. Half of T2D diagnoses in breast cancer survivors are attributable to the cancer therapy itself. The underlying mechanisms of tamoxifen-induced T2D are unknown. We hypothesized that the detrimental impact of tamoxifen on insulin sensitivity was mediated by changes in the liver and skeletal muscle, and was exacerbated by high fat diet (HFD). Ovariectomized female mice supplemented with estradiol were randomized to low fat diet (LFD), LFD + tamoxifen, HFD, or HFD + tamoxifen. In general, our preclinical model recapitulated the observations from epidemiological studies on breast cancer survivors. HFD + tamoxifen mice had greater body fat percentage and fasting glucose (P < 0.02 for the HFD-Tamoxifen interaction). The HFD + tamoxifen mice developed insulin resistance determined by HOMA-IR (P < 0.01) and tended towards impaired glucose tolerance measured by glucose AUC from a glucose tolerance test (P = 0.1). In the liver of HFD-fed mice, tamoxifen resulted in greater accumulation of triacylglycerol (P = 0.01) which correlated positively with HOMA-IR (R2= 0.4; P < 0.001). Gastrocnemius citrate synthase activity was elevated with tamoxifen treatment independent of diet, as was phosphorylation of AMP-activated kinase (P < 0.05). HFD + tamoxifen mice had lower content of muscle mitochondrial complex II (P = 0.05) and complex V (P = 0.1). These data suggest that the potential mechanisms underlying tamoxifen-induced T2D is ectopic hepatic fat accumulation and lowered skeletal muscle mitochondrial content. Importantly, this study reveals a difference in response to tamoxifen between lean and obese females. Future studies will explore interventions that can be combined with tamoxifen to prevent hepatosteatosis and protect skeletal muscle mitochondria with the goal of reducing T2D in breast cancer survivors. Disclosure R.L. Scalzo: None. S.E. Hull: None. J.E.B. Reusch: Board Member; Self; American Diabetes Association. Other Relationship; Self; Merck & Co., Inc. P. MacLean: Advisory Panel; Self; Habit LLC. E. Wellberg: None. Funding Susan G. Komen Foundation; National Institutes of Health